Category: Imported News

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E-diary vs Paper Diary in Binge Eating Disorder

Conditions: Binge Eating Disorder

Interventions: Other: The subject will complete e-diary for 2 weeks; Other: complete paper diary for 2 weeks

Sponsors: Lindner Center of HOPE; SignanthHealth; The Lindner Center of HOPE

Recruiting
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Transition Care for FEP

Conditions: Schizoaffective Disorders; Bipolar Disorder With Psychotic Features; Schizophrenia Disorders; Major Depressive Disorder With Psychotic Features; Psychosis NOS

Interventions: Behavioral: Transition Care Team

Sponsors: University of Chicago; Sidney R. Baer, Jr. Foundation

Recruiting
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StockWatch: Lilly’s Up-to-$3.8B Deal for AtaiBeckley a Good Trip for Psychedelic Drugs, Analysts and Investors Agree

It wasn’t too long ago that biopharma giants stayed away from developing psychedelic drugs—but positive clinical data plus a friendlier regulatory climate in Washington have prompted the largest drug developers to embrace the field.

The latest and most telling example of pharma embracing psych drugs came when Eli Lilly (NYSE: LLY) announced that it agreed to acquire AtaiBeckley (Nasdaq: ATAI) for up to $3.8 billion—of which Lilly will pay $2.8 billion upfront. The deal, set to close in the third quarter, expands Lilly’s neuroscience portfolio by adding the pipeline of AtaiBeckley led by BPL-003 (mebufotenin benzoate), a Phase III candidate for treatment-resistant depression (TRD) that is a synthetic form of 5-MeO-DMT administered intranasally. BPL-003 has been granted the FDA’s Breakthrough Therapy designation.

BPL-003 wowed analysts and others back in April after AtaiBeckley published positive data from a Phase IIa trial (NCT05660642) showing that a single intranasal dose of BPL-003 led to rapid and sustained reductions in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline in 12 TRD patients who remained on stable SSRI therapy throughout the study. Both the six patients dosed at 10 mg and six at 12 mg showed a 66.7% antidepressant response rate (defined as ≥50% reduction from baseline MADRS score) at Day 2, with five of six participants in the 10 mg cohort (83%) and four of six in the 12 mg cohort (66.7%) maintaining their response at Week 12.

“Especially with progress on BPL-003, we see the company as positioning itself well to becoming a significant player in the mental health therapeutics space,” Sumant Kulkarni, a senior analyst covering biotechnology with Canaccord Genuity, wrote on news of the positive data, adding: “We also still see this space as large enough to accommodate multiple approaches/competitors.”

$3.7B in projected peak sales

Kulkarni also raised Canaccord Genuity’s peak unadjusted U.S. sales forecast for BPL-003 to $3.7 billion by 2036 from $2 billion, after revising the firm’s model by raising the list price from $20,000 to $30,000 per annual treatment course (not accounting for insurance coverage), about the same price as Spravato® (esketamine), also a nasal spray marketed by Johnson & Johnson (NYSE: JNJ) for TRD plus some depressive symptoms in adults with major depressive disorder (MDD).

Spravato, a noncompetitive N-methyl D-aspartate (NMDA) receptor antagonist, crossed the $1 billion sales threshold during the second quarter, as it generated $584 million, up 25% quarter-over-quarter from $464 million in Q1—and up 43% from $734 million in the first half of 2025.

“Sales are tracking to reach annual sales guidance of $3-3.5B+ by 2027–28,” Jefferies equity analyst Andrew Tsai wrote in a research note focused on J&J’s second-quarter results. “Spravato’s trajectory supports the notion psychedelics can be commercially viable in hard-to-treat mental health disorders, by leveraging JNJ’s infrastructure.”

Given the data for BPL-003, Lilly got a bargain, Tsai wrote in a separate note on the Lilly-AtaiBeckley acquisition.

“We think the deal heavily favors LLY, as ATAI’s lead asset BPL-003 (intranasal 5-MeO-DMT) should have multibillion dollar peak sales potential,” Tsai wrote, rather than the $1 billion-plus that he thinks was implied by the deal price.

Tsai and Jefferies had previously forecast peak sales of between $1 billion and $2 billion—a range he said was “arguably conservative” since BPL-003 could, if it aces its Phase III trial, show superiority to Spravato, which is on track to reach up to $5 billion-plus in peak sales.

Positive implications

“At the same time, we appreciate LLY has significantly more resources to maximize the long-term value of ATAI’s psychedelic assets. In any case, the deal has (+) [positive] implications for the entire psychedelic space,” Tsai added.

Among pharma giants joining J&J in embracing psychedelic drug development in recent years:

  • AbbVie (NYSE: ABBV), which last year acquired the lead pipeline program of privately held Gilgamesh Pharmaceuticals, the moderate-to-severe MDD candidate bretisilocin (GM-2505), for up to $1.2 billion.
  • Otsuka Holdings (Tokyo Stock Exchange: 4578), which in 2023 acquired Mindset Pharma, a Canadian psych drug developer focused on psychiatric and neurological disorders, for C$80 million ($56 million).

With its deal for AtaiBeckley, Lilly becomes the latest pharma giant to perceive the positive implications Tsai cited.

“Treatment-resistant depression persists even after multiple treatments have failed. Millions of people are still searching for relief and desperately need a therapy that works,” Carole Ho, executive vice president and president, Lilly Neuroscience, said in a statement. “Advancing AtaiBeckley’s investigational therapies gives us a real chance to change that.”

Investors agreed with Lilly, giving the pharma a 1% increase Thursday, the day the acquisition was announced, from $1,156.63 to $1,169.17—no small feat since buyers typically stay flat or see their shares slide after announcing an acquisition. And not surprisingly, AtaiBeckley investors were enthusiastic about the deal, as its stock leaped 33% from $5.36 to $7.15. On Friday, Lilly inched up 0.8% to $1,178.58 while AtaiBeckley rose 1% to $7.22.

The AtaiBeckley buyout is Lilly’s eighth announced acquisition of a smaller biopharma this year.

Lilly is acquiring three infectious diseases vaccine developers—Vaccine Company for up to $1.55 billion, Curevo for up to $1.5 billion, and LimmaTech Biologics for up to $780 million—as well as in vivo chimeric antigen receptor T-cell (CAR T) developer Kelonia Therapeutics for up to $7 billion); JAK inhibitor developer Ajax Therapeutics for up to $2.3 billion; next-generation dual-payload antibody-drug conjugate (ADC) developer CrossBridge Bio for up to $300 million; and nonviral DNA delivery-focused drug developer Engage Biologics for up to $202 million cash.

The deal spree reflects Lilly’s desire to capitalize on the billions of dollars it is generating from sales of its obesity and diabetes drugs based on glucagon-like peptide 1 (GLP-1) receptor agonists alone or in tandem with a glucose-dependent insulinotropic polypeptide (GIP).

“If we see great ideas that we think we can use to help people that need them, of course we’ll do deals,” Daniel M. Skovronsky, MD, PhD, Lilly’s chief scientific and product officer and president of Lilly Research Laboratories, said on CNBC.

“Positive development”

David Risinger, a senior managing director and senior research analyst covering diversified biopharmaceuticals at Leerink Partners, said his firm viewed Lilly’s buyout of AtaiBeckley “as a positive development because it enhances LLY’s pipeline of potential neuroscience blockbuster candidates.”

That pipeline is led by five Phase III programs involving four drugs, none of them a psychedelic. Two of the programs belong to brenipatide, a dual agonist of both the GIP and GLP-1 receptors. Brenipatide is being developed for both MDD and alcohol use disorder.

Also in Lilly’s late-stage neuroscience pipeline are:

  • Donanemab, which binds to deposited amyloid plaque in the brain and is being studied for the treatment of cognitively unimpaired Alzheimer’s disease.
  • Ixoberogene Soroparvovec (Ixo-Vec), an intravitreal gene therapy being studied as a single one-time treatment for vision loss associated with neovascular (wet) age-related macular degeneration (AMD).
  • Remternetug (LY3372993), which also binds to deposited amyloid plaque in the brain and is under study as a treatment of cognitively unimpaired/mild cognitive impairment due to Alzheimer’s disease, with potential for subcutaneous delivery.

In addition, AtaiBeckley “would provide ​differentiated exposure in psychiatry and reinforce [Lilly’s] ​broader effort to diversify beyond ​its cornerstone cardiometabolic franchise,” observed Evan David Seigerman, a managing director and head of healthcare research at BMO Capital Markets, as reported by Reuters.

AtaiBeckley was formed last November by the merger of atai Life Sciences and Beckley Psytech. The company’s stock has nearly doubled, soaring 98% over the past six months from $3.64 on January 16.

“Going mainstream”

“Psychedelic Medicine is going mainstream,” declared Steve Jurvetson, co-founder of Future Ventures, in a post on X. Jurvetson and Future were among early investors, along with Peter Thiel in atai Life Sciences.

AtaiBeckley is one of numerous psychedelic drug developers to show significant six-month gains since January: As of Friday’s closing bell, Compass Pathways (Nasdaq: CMPS) shares jumped 68% to $12.35, GH Research ballooned 69% to $28.71, while Definium Therapeutics (Nasdaq: DFTX) nearly tripled, zooming 194% to $44.29.

Interestingly, those three companies did not get a solid bounce from AtaiBeckley’s acquisition by Lilly. Since the deal was announced Thursday, Compass fell 7% from $13.31 pre-announcement, Definium dipped 3% from $45.66. GH rose 8% Thursday from $26.92 to $29.13, before sliding 1.4% the following day.

Bucking the trend was Cybin, d/b/a Helus Pharma (Nasdaq: HELP), which has climbed 11% since the Lilly-AtaiBeckley announcement, from $6.51 to $7.25. Its shares have slumped 6% since January—but soared 58% over the past month on positive news, such as the 88%+ enrollment rate of patients in Helus’ Phase III APPROACH pivotal trial (NCT06564818) of HLP003 in MDD, on track for topline data readout in Q4 2026.

“We see the potential for 150–200% upside [jump in stock price] if Phase III data in 4Q26 are positive,” Kulkarni wrote, making it the largest potential jump among psychedelic drug developers.

In addition to favorable data, the stock surges also reflect actions by President Donald J. Trump’s administration to encourage psychedelic drug development. In April, President Trump signed Executive Order 14401, directing the FDA and other federal agencies to accelerate research and improve access to psychedelic drugs, citing their potential as promising treatments for serious mental illnesses.

And on July 13, the FDA published “Psychedelic Drugs: Considerations for Clinical Investigations,” a final guidance designed to provide general considerations for developers of psych drugs, with recommendations for how to conduct clinical trials for the treatments.

“Rather than providing specific recommendations on study design, this guidance will present foundational constructs that all sponsors studying the therapeutic potential of psychedelic drugs, including sponsors without commercial drug development as primary interest (e.g., academic researchers), should consider,” the FDA wrote in the final guidance. “Sponsors are encouraged to request meetings with FDA for advice on a specific drug development program.”

Leaders and laggards

  • Q32 Bio (Nasdaq: QTTB) shares nearly doubled, leaping 91% from $11.21 to $21.38 July 13 after the autoimmune and inflammatory disease drug developer announced positive 36-week topline results from Part B of the Phase IIa SIGNAL-AA trial (NCT06018428) assessing bempikibart in patients with severe or very severe alopecia areata. Q32 said it saw clinically meaningful efficacy data on the primary endpoint of mean percent change from baseline in SALT score, with a reduction from baseline of 35.3% in the prespecified modified intent to treat (mITT) analysis. The company also reported that 40.0% of patients (10/25) achieved SALT-20 response at Week 36 in the mITT analysis, while 30.3% of patients (10/33) achieved SALT-20 response at Week 36 in the ITT analysis of all enrolled patients.
  • Veradermics (NYSE: MANE) shares yo-yoed this past week, climbing 12% from $110.17 to $123.70 Wednesday after the pattern hair loss drug developer announced positive topline results from its open-label Phase II Study 207 trial (NCT06527365) assessing VDPHL01, an extended-release oral minoxidil formulation, in women with mild-to-moderate pattern hair loss. Veradermics said most study participants reported improved hair coverage at Month 2, with approximately 88.9% of patients dosed once daily and 90.0% dosed twice daily reporting “improved” or “much improved” outcomes at Month 6. Participants dosed once daily showed a mean increase in non-vellus target area hair count (TAHC) of 22.7 hairs/cm² at Month 6, an average that rose to 23.3 hairs/cm² in twice daily dosed patients. The mini surge was short-lived, however, as investors more than gave back the gain, selling off shares to send them tumbling 14% to $105.83 Thursday amid possible investor questions about whether the good clinical news was already reflected in the stock price.

The post StockWatch: Lilly’s Up-to-$3.8B Deal for AtaiBeckley a Good Trip for Psychedelic Drugs, Analysts and Investors Agree appeared first on GEN – Genetic Engineering and Biotechnology News.

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Opinion: Beware the unintended consequences of testosterone screening for military servicemembers

When I first heard the announcement on Wednesday that the Department of Defense will begin a mandatory testosterone screening program for service members, my mind naturally leapt to a series of questions derived from my career studying men’s health and population-level screening in men’s health. In particular, I fear that the widespread rollout of testosterone screening may lead to some surprising and unintended consequences that must be carefully weighed if we want to prioritize the health of U.S. servicemembers.

As a practicing urologist and health outcomes researcher, I have seen firsthand how testosterone supplementation has received growing interest in recent years. I have also studied the impacts and implementation other types of screening tests, including among military servicemembers.  As with any type of population-level medical screening, a careful examination of risks and benefits is vital.

Read the rest…

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Organ Aging Linked to Breakdown in Immune Cell Interaction and Senescent Neutrophil Clearance

We may age at different rates, but none of us escapes aging. A study in mice and in human cells by Stanford Medicine researchers has linked organ aging to the increased inability—with advancing age—of tissue resident macrophage (TRM) immune cells to clear aged neutrophils, another type of immune cell.

The study found that these TRMs appear to be central coordinators of age-related organ decline. Blocking a single receptor, EP2, on these cells preserved the youthfulness of multiple organs in mice, including the brain, heart, skeletal and heart muscle, liver, spleen, bone marrow, kidney, and colon. The receptor binds specifically to a hormone, prostaglandin E2, which is known to cause inflammation and pain in humans as well as in mice.

The researchers found that in mice, selectively disabling this receptor exclusively on tissue-resident macrophages genetically, or using an experimental selective EP2 antagonist drug, prevented chronic-inflammation-driven disorders of age—including frailty, excessive fat accumulation, and heart trouble—and also substantially slowed cognitive decline.

Research lead Katrin Andreasson, MD, the Edward F. and Irene Thiel Pimley Professor in Neurology and Neurological Sciences, said, “We’ve shown that when tissue-resident macrophages don’t have EP2 on their surfaces anymore or when that receptor is plugged up by a drug, this decline doesn’t happen … We’ve been trying to figure out why we age. Now we know at least one big reason for it.”

The discoveries help to clarify systemic inflammation’s significant contribution to aging and the debilities that accompany it. The findings also point to a pharmaceutical approach that could restrain our organs’ unavoidable march toward senescence and so extend overall health span.

Senior author Andreasson, together with first author Jessy Tan, PhD, an instructor in neurology, and colleagues reported on their findings in Science, in a paper titled “Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging.” In their research article summary, the team stated, “This work identifies EP2 signaling in TRMs as a central regulator of organ-wide aging through its control of senescent neutrophil clearance, reframing aging as a failure of active cellular clearance rather than passive degeneration.”

Aging is accompanied by parallel functional decline across organs, but the cellular drivers remain unclear, the authors wrote. “Although molecular hallmarks of aging have been identified, the cellular events that initiate and propel tissue decline remain poorly defined.”

The most abundant white blood cells in our immune system are neutrophils, which act as the body’s main first responders. Produced in bone marrow, new neutrophils are transferred to the bloodstream, where they circulate and attack bacterial, viral, or fungal pathogens that they encounter. Neutrophils are also extremely short-lived, surviving just 12–24 hours.

Some 90% of circulating neutrophils end up in the liver, spleen, and bone marrow, awaiting execution clearance by another type of immune cell. “Neutrophils are among the shortest-lived immune cells, aging within hours in the circulation and requiring continuous clearance,” the team noted.

This neutrophil clearance is critical. In aged animals, the vast bulk of neutrophils that never see combat undergo a fast transition to senescence, a zombie-like state in which they may injure, age, and inflame neighboring cells. And as we age, the neutrophil count rises, with senescent neutrophils constituting an ever higher percentage. “Senescent neutrophils are killing our tissues,” Andreasson said. “Clearance of these cells is essential for preventing chronic inflammation.”

That’s a job for macrophages. These cells comb the tissues for pathogens, signal other cells to lend a hand in the fight, and pump out growth factors that help repair damaged tissue. But first and foremost, Andreasson said, “They’re the body’s garbage collection crew. A lot of that garbage is defunct cells.” And a lot of those cells are neutrophils—to the tune of 100 billion a day.

Macrophages come in several subtypes. Tissue-resident macrophages are long-lived and ubiquitous. They take up residence in each of the body’s organs during fetal development and remain for their lifetimes in whatever organ they’ve inhabited, adapting their roles to fit that organ.

One of tissue-resident macrophages’ prime responsibilities is to swallow senescent cells. “A core TRM function is efferocytosis, the clearance of apoptotic, senescent, and damaged cells that is essential for preventing chronic inflammation,” they explained. Especially important targets for this operation, the study showed, are the potentially 100 billion neutrophils produced daily, which start showing signs of senescence within 8 to 12 hours after entering the bloodstream. (Neutrophils that haven’t arrived at senescence yet but have lived long enough and seen enough to put out “kill me now” flags of surrender on their cell surfaces are fair game.)

“Among primary TRM targets are neutrophils, the most abundantly produced immune cell, with more than 10 billion and 100 billion generated daily in mice and humans, respectively,” the investigator noted. “Uncleared aged neutrophils release proteases and extracellular traps that damage tissues, propagate inflammation, and promote aging, and are normally removed efficiently by TRMs in the liver, spleen, and bone marrow.”

But tissue-resident macrophages also grow old. As Andreasson and associates showed in a prior study, over the advancing years these long-lived cells become ever more prone to succumb to aging-associated inflammation and to propagate it. In their newly reported paper, they noted, “TRMs comprise 60–90% of macrophages in the brain, liver, lungs, heart, and kidneys, and their long lifespan makes them particularly vulnerable to aging, as they accumulate metabolic, oxidative, and inflammatory injury over years to decades.”

Immune cells produce hormones called prostaglandins. One of the five varieties of prostaglandin, called PGE2, can exert diverse effects on a cell, depending on which type of surface receptor is expressed on that cell’s surface. Of the various subtypes of receptors for PGE2, the EP2 receptor is highly pro-inflammatory. Tissue-resident macrophages are loaded with EP2.

Infection, injury, and toxic chemicals, including those produced by our aging bodies, increase PGE2 output. As the team’s prior work showed, that output grows substantially as we grow older. So does the concentration of EP2 on tissue-resident macrophages. “TRMs express the prostaglandin E2 (PGE2) receptor EP2, which suppresses macrophage metabolism and phagocytosis in aging,” the investigators noted.

This effectively creates a one-two punch. PGE2’s pro-inflammatory influence increases with age. The resulting unrelenting inflammatory PGE2 stimulation on tissue-resident macrophages, the new study showed, downshifts these cells’ ability to clear neutrophils. Senescent neutrophils then accumulate in tissues and blood.

Andreasson and her colleagues had previously shown that with aging, tissue-resident macrophages undergo a slow decay in their energy metabolism. “Once that starts, there’s a steady decline in a macrophage’s performance,” she said.

For their newly reported study, Andreasson’s lab bioengineered a mouse in which, at a time of the scientists’ choosing, the EP2 gene gets deleted—but only in tissue-resident macrophages. The results of their experiments showed that disappearance of EP2 from these cells reinvigorated the neutrophil-clearance process that PGE2 undermines.

For their experiments, the Stanford Medicine researchers studied younger normal mice, aged 6–8 months, which corresponds to late adolescence or early adulthood in humans, and they also studied older normal mice, at 23 to 25 months of age, whose human counterparts would be in their 60s or 70s. They also looked at older mice whose EP2-encoding gene had been deleted at 4 to 6 months of age (equivalent to their “teenage” years).

The team’s analyses identified 71 proteins, found in blood, whose levels were significantly altered in older normal mice. Of those proteins, 59 stayed at youthful levels in older mice whose tissue-resident macrophages lacked EP2. Many of these proteins originated in the liver. “The liver is one of the body’s most tissue-resident-macrophage-enriched organs and a major contributor to aging-related changes in blood chemistry,” Andreasson said. “It’s the central organ determining the body’s metabolic rate.”

The study showed that in normal old mice, smoldering senescent neutrophils accumulated in the liver, spleen, and bone marrow and, to a lesser extent, in many other organs the researchers looked at.

But the organs of older mice lacking EP2 on their tissue-resident macrophages retained the lower neutrophil numbers of youth. These mice looked younger, leaner, and more physically fit compared with control littermates. They evidenced less visceral fat and greater muscle mass. Their performance on tests of multiple organs’ function equaled that of young mice.

EP2 deletion in addition reduced inflammation in the blood, liver, colon, heart, kidney, and hippocampus (a brain region tightly tied to memory and navigation ability) in the older mice. Their speed, balance, and forelimb grip strength resembled that of young animals.

Reducing EP2 activity in older mice also preserved their memory capabilities. These animals could thread their way through a maze or recall previously encountered objects almost as well as younger mice—and far better than similarly old mice with tissue-resident macrophages expressing functional EP2. “Reducing TRM EP2 signaling in aged mice preserved youthful mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment, and systemic inflammation,” they wrote in summary.

There are, today, no approved drugs that selectively shut down EP2 activity, although there are several that target PGE2. Non-steroidal anti-inflammatory painkillers work by blocking PGE2 production, Andreasson said. That’s how aspirin and similar drugs reduce pain, fever, swelling, and redness. But to greater or lesser degrees these drugs all block other vital prostaglandins. Even PGE2 has beneficial properties when it binds to receptors other than EP2, rather than the detrimental inflammatory one examined in this study.

As part of their study, the investigators treated otherwise normal 22-month-old mice for two months with an EP2-inhibiting experimental drug. The results showed that the treatment reduced total and senescent neutrophil counts in old mice toward youthful levels. In culture dishes, old age diminished—but the EP2-blocking drug likewise significantly restored—the mice’s tissue-resident macrophages’ ability to engulf and digest burnt-out neutrophils. “Together, these results demonstrate that pharmacologic EP2 inhibition partially reverses age-associated TRM dysfunction and senescent neutrophil accumulation, with strongest rescue in the liver,” they stated.

Finally, the team turned to a large human database characterizing different cell types in young, old, and diseased human livers. This database revealed the same age-related neutrophil buildup, increased neutrophil senescence, tissue-resident-macrophage decline, and heightened EP2 activity in older—and even more so, diseased—livers that the Stanford Medicine researchers had seen in mice. This was a first-time observation in human cells, according to Andreasson. “These human findings, while correlative, position the TRM EP2-efferocytosis axis as a candidate mechanism in human aging that warrants further functional testing,” they noted. “Specifically, future studies should assess whether the impaired clearance of senescent neutrophils also occurs in human TRMs and whether pharmacological EP2 blockade can restore this defect.”

Andreasson suggested that targeting neutrophil clearance may yield big therapeutic benefits. “We need to develop a safe drug that incapacitates EP2 without disrupting upstream events such as PGE2 production.”

The post Organ Aging Linked to Breakdown in Immune Cell Interaction and Senescent Neutrophil Clearance appeared first on GEN – Genetic Engineering and Biotechnology News.

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Opinion: STAT readers on the value of primary care, obesity as a disease, and more

First Opinion is STAT’s platform for interesting, illuminating, and provocative articles about the life sciences writ large, written by biotech insiders, health care workers, researchers, and others.

To encourage robust, good-faith discussion about issues raised in First Opinion essays, STAT publishes selected Letters to the Editor received in response to them. You can submit a Letter to the Editor here, or find the submission form at the end of any First Opinion essay.

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Circuit logic of oxytocin and vasopressin complementary actions

Oxytocin (OT) and vasopressin (VP) are evolutionarily conserved neuropeptides that regulate social behavior, emotional processing and physiological homeostasis. Although traditionally studied as individual modulators of affiliation, stress and autonomic function, emerging evidence indicates that their actions are best understood at the level of neural circuits. Advances in optogenetics, cell-type-specific electrophysiology and systems neuroscience have revealed that OT and VP act within distributed networks through receptor-defined microcircuits composed of excitatory and inhibitory neuronal populations, astrocytes and long-range projections. Within these circuits, OT and VP can exert complementary, synergistic or opposing effects depending on receptor localization, cellular identity and network state. Here, we synthesize recent circuit-level and electrophysiological evidence to propose a framework in which OT and VP operate as a coordinated neuromodulatory axis. We argue that the functional consequences of OT/VP signaling emerge not from peptide identity alone, but from their engagement of recurrent circuit motifs that redistribute excitation and inhibition across neural networks. These motifs provide a mechanistic substrate for regulating transitions between competing behavioral and physiological states, including social safety vs. threat, affiliation vs. avoidance, and parasympathetic vs. sympathetic dominance. We further discuss how disruption of receptor topology, synaptic integration and circuit architecture may contribute to neurodevelopmental, psychiatric and stress-related disorders. By shifting the focus from peptide-centric models to circuit-level mechanisms, this framework reconciles seemingly contradictory findings across brain regions and behavioral paradigms, and provides a foundation for the development of next-generation circuit-based therapeutic strategies targeting the oxytocin-vasopressin axis.